Method of contact coating a microneedle array

ABSTRACT

A method of coating a microneedle array by applying a coating fluid using a flexible film in a brush-like manner. A method of coating a microneedle array comprising: providing a microneedle array having a substrate and a plurality of microneedles; providing a flexible film; providing a coating solution comprising a carrier fluid and a coating material; applying the coating solution onto a first major surface of the flexible film; performing a transfer step of bringing the first major surface of the flexible film into contact with the microneedles and removing the flexible film from contact with the microneedles; and allowing the carrier fluid to evaporate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/718,474, filed May 2, 2007, now U.S. Pat. No. 8,057,842, which is anational stage filing under 35 U.S.C. 371 of PCT/US2005/041993, filedNov. 18, 2005, which claims priority to U.S. Provisional ApplicationSer. No. 60/629,187, filed on Nov. 18, 2004, which disclosure of whichis incorporated herein by reference in their entirety.

FIELD

The present invention relates to methods of coating a microneedle array.

BACKGROUND

Only a limited number of molecules with demonstrated therapeutic valuecan be transported through the skin, even with the use of approvedchemical enhancers. The main barrier to transport of molecules throughthe skin is the stratum corneum (the outermost layer of the skin).

Devices including arrays of relatively small structures, sometimesreferred to as microneedles or micro-pins, have been disclosed for usein connection with the delivery of therapeutic agents and othersubstances through the skin and other surfaces. The devices aretypically pressed against the skin in an effort to pierce the stratumcorneum such that the therapeutic agents and other substances can passthrough that layer and into the tissues below.

Microneedle devices having a fluid reservoir and conduits through whicha therapeutic substance may be delivered to the skin have been proposed,but there remain a number of difficulties with such systems, such as theability to make very fine channels that can reliably be used for fluidflow.

Microneedle devices having a dried coating on the surface of amicroneedle array have desirable features compared to fluid reservoirdevices. The devices are generally simpler and can directly inject atherapeutic substance into the skin without the need for providingreliable control of fluid flow through very fine channels in themicroneedle device.

SUMMARY OF THE INVENTION

The ability to provide a consistent coating in one or more desiredlocations on the microneedle array is an important feature for amicroneedle device having a dried coating. Although there are numerouswell known methods for providing dried coatings on generally flatsurfaces, coating of a microneedle array provides a challenge due to thehigh surface irregularity inherent in any array design.

It has now been found that the location of a dried coating depositedfrom a coating fluid may be adjusted and controlled by bringing amicroneedle array into direct contact with a coating substrate having anapplied coating formulation. In one embodiment, the location of a driedcoating deposited from a coating fluid may be adjusted and controlled byapplying the coating fluid using a flexible film in a brush-like manner.

In a first aspect, the present invention provides a method of coating amicroneedle array comprising providing a microneedle array having asubstrate and a plurality of microneedles, providing a flexible film,providing a coating solution comprising a carrier fluid and a coatingmaterial, applying the coating solution onto a first major surface ofthe flexible film, performing a transfer step of bringing the firstmajor surface of the flexible film into contact with the microneedlesand removing the flexible film from contact with the microneedles; andallowing the carrier fluid to evaporate.

In a second aspect, the present invention provides a method of coating amicroneedle array comprising providing a microneedle array having asubstrate and a plurality of microneedles. A coating solution comprisinga carrier fluid and a coating material is provided and applied onto afirst major surface of a coating substrate to form a layer of appliedcoating solution having a thickness equal to or less than the height ofat least one of the microneedles. A coating apparatus is providedcomprising a coating substrate and a supporting member for themicroneedle array, wherein at least one of the coating substrate and themicroneedle array is flexibly mounted within the coating apparatus. Atransfer step is performed by bringing the first major surface of thecoating substrate into contact with the microneedles and removing thecoating substrate from contact with the microneedles, therebytransferring at least a portion of the coating solution to themicroneedle array. The transferred carrier fluid is allowed toevaporate.

As used herein, certain terms will be understood to have the meaning setforth below:

“Array” refers to the medical devices described herein that include oneor more structures capable of piercing the stratum corneum to facilitatethe transdermal delivery of therapeutic agents or the sampling of fluidsthrough or to the skin.

“Microstructure,” “microneedle” or “microarray” refers to the specificmicroscopic structures associated with the array that are capable ofpiercing the stratum corneum to facilitate the transdermal delivery oftherapeutic agents or the sampling of fluids through the skin. By way ofexample, microstructures can include needle or needle-like structures aswell as other structures capable of piercing the stratum corneum.

The features and advantages of the present invention will be understoodupon consideration of the detailed description of the preferredembodiment as well as the appended claims. These and other features andadvantages of the invention may be described below in connection withvarious illustrative embodiments of the invention. The above summary ofthe present invention is not intended to describe each disclosedembodiment or every implementation of the present invention. The Figuresand the detailed description which follow more particularly exemplifyillustrative embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention will now be described in greaterdetail below with reference to the attached drawings, wherein:

FIG. 1 is a schematic cross-sectional view of one embodiment of thepresent invention during the transfer step.

FIGS. 2A and 2B are a schematic plan and cross-sectional view,respectively, of the transfer step of one embodiment of the presentinvention.

FIGS. 2C and 2D are a schematic plan and cross-sectional view,respectively, where the microneedle array has been rotated in betweenmultiple transfer steps.

FIGS. 3A and 3B are schematic plan views of another embodiment of thepresent invention.

FIG. 4 is a schematic perspective view of patch microneedle device.

FIG. 5 is a scanning electron micrograph of a coated microneedle array.

FIGS. 6A and 6B are schematic perspective views of a portion of acoating apparatus in various embodiments of the present invention.

FIG. 6C is a schematic cross-sectional view of a portion of anotherembodiment of a coating apparatus.

FIG. 7A is a schematic perspective view of a portion of a coatingapparatus in one embodiment of the present invention.

FIGS. 7B and 7C are schematic cross-sectional views of a portion of acoating apparatus in various embodiments of the present invention.

FIGS. 8A, 8B, and 8C are schematic cross-sectional views of the transferstep of another embodiment of the present invention.

FIGS. 9A to 9E are schematic cross-sectional views of alternativeembodiments for supporting a flexible film coating substrate.

FIGS. 10A, 10B, and 10C are schematic cross-sectional views of thetransfer step of another embodiment of the present invention.

FIG. 11 is a schematic cross-sectional view of another embodiment of thepresent invention that employs an extrusion die.

FIGS. 12A and B are schematic cross-sectional views of other embodimentsof the present invention that employ a pickup roll.

FIG. 13 is a schematic cross-sectional view of another embodiment of thepresent invention that employs a partner roll.

FIGS. 14A and 14B are schematic cross-sectional views of a portion of acoating apparatus in another embodiment of the present invention.

FIG. 15A is a schematic cross-sectional view of another embodiment ofthe present invention that employs a pickup plate.

FIG. 15B is a schematic plan view of the embodiment in FIG. 15A wherethe pickup plate has a herringbone capillary pattern.

FIG. 16A is a schematic cross-sectional view of another embodiment ofthe present invention that employs a pickup plate and an extrusion die.

FIG. 16B is a schematic plan view of the embodiment in FIG. 16A.

FIGS. 17A and 17B are schematic cross-sectional views of variousdoctoring features.

DETAILED DESCRIPTION

One aspect of the method of the present invention is shown in FIG. 1. Amicroneedle array 250 is provided having a substrate 220 andmicroneedles 230 extending from the substrate. A coating solution 210has been applied to the first major surface 205 of a flexible film 200prior to the illustrated transfer step. The coating solution 210comprises a carrier fluid and a coating material. The flexible film 200serves as a flexible coating substrate and has a leading edge 202 thatis connected to a source of movement and a trailing edge 204 that isbrought into contact with the microneedles 230 during the transfer step.As shown, the flexible film 200 with coating solution 210 is oriented sothat the coating solution 210 contacts the microneedles 230 when thefilm 200 is brought into contact with the tips of the microneedles. Thefilm is moved in a linear direction across the array in the direction ofthe arrow shown in FIG. 1. After the film has been moved across the areaof the array that is desired to be coated, it is then removed and thecarrier fluid is allowed to evaporate, thereby leaving dried coatingmaterial on the microneedle array 250. The leading edge 202 portion ofthe flexible film 200 is oriented at a flexure angle, 240, with respectto the substrate 220 as shown.

In one embodiment the microneedle array is oriented so that themicroneedles are facing upward and the coating solution on the flexiblefilm is facing downwards when it is brought into contact with themicroneedles. The terms upwards and downwards refer to orientation withrespect to gravity. That is, the force of gravity will cause theflexible film to rest on the microneedle array when the flexible film isfacing downwards. This orientation need not be precisely aligned withrespect to gravity, but need only be sufficient such that the flexiblefilm may rest on the microneedle array due to the force of gravityalone. In one embodiment, the microneedle array is oriented so that itis perpendicular to the force of gravity. In one aspect, an optionalsupporting member may be attached to the flexible film, and inparticular to the upper surface of the trailing edge of the film, toassist the contact between coating solution and microneedles.

Although the flexible film is shown moving in a linear direction acrossthe microneedle array during the transfer step, it may be moved in anon-linear fashion, such as in a curved or stepwise motion, to adjustthe amount and location of deposited coating material or to simplify themanufacturing process.

In one embodiment, a coating apparatus is used wherein the flexible film200 may be mounted on a rotational arm 320 such that it contacts themicroneedles 230 during one part of a rotation (shown in FIG. 3A) andsuch that additional coating solution is added to the film 200 from afluid reservoir 300 during another part of the rotation (shown in FIG.3B). The amount of coating solution added to the flexible film from thefluid reservoir is desirably about the same as the amount of coatingmaterial deposited on the microneedles. In another aspect, a reservoirmay be in direct fluid communication and/or contact with the flexiblefilm throughout the entire coating cycle so as to supply coatingsolution to the film continuously or on-demand, as desired. The flexiblefilm 200 as shown in FIGS. 1 and 3 is flexibly mounted in the coatingapparatus. One edge of the flexible film is rigidly held on therotational arm, thus leaving the other (trailing) edge of the film tofreely flex as it contacts the microneedle array (i.e., the trailingedge of the film is flexibly mounted). The trailing edge will generallybe aligned so that it moves in a plane parallel to and below a planeformed by the tips of the microneedle array, so that it will interferewith the array and flex when it comes into contact with the array (asshown in FIG. 1). This distance between the plane of motion of thetrailing edge and the a plane formed by the tips of the microneedlearray is referred to as the edge-array interference and is typicallybetween about 50 and 1000 μm, sometimes between about 200 and about 500μm.

The transfer step shown may be repeated one or more times in order totransfer additional coating material to the microneedle array 250. Themicroneedle array may be moved with respect to the direction of motionof the film movement in between the repeated steps. This is shown inFIGS. 2A-2D where the microneedle array is shown with directionalindicators (A, B, C, D) to indicate orientation of the array. A firsttransfer step is shown in FIGS. 2A and 2B where the flexible film ismoved in the direction from A to C. The microneedle array is thenrotated approximately 90° prior to the transfer step shown in FIGS. 2Cand 2D where the flexible film is moved in the direction from D to B.This procedure may be repeated so that a subsequent step, for instance,would have the flexible film moving in the direction from C to A. Ofcourse, it is equally valid to hold the microneedle array fixed andchange the direction of motion of the flexible film, as it is therelative motion between the two that is of importance. Any combinationof transfer steps and rotational movements are suitable. Although therotation shown in FIG. 2C is approximately 90°, rotational movements maybe of any other amount. In a preferred embodiment transfer steps androtational movements are alternated on a one-to-one basis. In oneembodiment the size of each rotational movement is selected so as to beevenly divisible into 360° (e.g., 30°, 45°, 60°, 90°, 120°, 180°, etc.)and more preferably so that the total rotational movement sums to 360°less the size of a single rotational movement. For instance, using theorientational markings shown in FIG. 2A, the following sequence may beused where the transfer steps all occur in the direction shown by thearrow: a transfer step in the direction A to C, a 90° clockwiserotational movement of the microneedle array, a transfer step in thedirection D to B, a 90° clockwise rotational movement of the microneedlearray, a transfer step in the direction C to A, a 90° clockwiserotational movement of the microneedle array, a transfer step in thedirection B to D.

FIGS. 3A and 3B show additional detail of a coating apparatus suitablefor performing the transfer step. A microneedle array with microneedles230 is shown held in a stationary position. A pivot axis 310 and pivotarm 320 hold a flexible film 200 carrying coating material (not shown)which is advancing across the microneedles 230 (shown in FIG. 3A) andthereby transferring coating material from the flexible film 200 to themicroneedles 230. The film is then rotated 180 degrees (shown in FIG.3B) and passed across a reservoir 300 of coating material. The flexiblefilm 200 is oriented so that it picks up additional coating materialfrom the reservoir 300. These steps may be repeated, that is, the filmwith coating material may again be rotated to alternately contact themicroneedles (and deposit coating material) and contact the reservoir(to pick up additional coating material).

Any combination of rotational and/or translational motion of theflexible film may be employed to both apply the coating solution ontothe film and to effect the transfer step. FIG. 6A shows a perspectiveview of a coating apparatus with a pivot axis 310 and a pivot arm 320holding a flexible film 200 with the large arrows indicating thedirection of rotation of the film in a horizontal plane containing themicroneedle array (not shown). Alternatively, the pivot arm 320 may beattached to a rotating disk 330 as shown in FIG. 6B. In still anotherembodiment (FIG. 6C), the film 200 may be directly attached to a roll340 that rotates in a plane perpendicular to the microneedle array 250.Likewise, any combination of rotational and/or translational motion ofthe microneedle array 250 may be employed to bring the microneedles intocontact with the flexible film 200. FIG. 7A shows a perspective view ofmicroneedle arrays 250 held on a rotating disk 345 that is employed toadvance the arrays 250 to a position 350 where they may be contacted bythe flexible film 200 (at a point where the flexible film is advancedanother 90 degrees from the orientation shown in the figure).Alternatively (FIG. 7B), the arrays may be held on a roll 360 thatrotates in a plane perpendicular to the plane of the microneedle array.As shown, the roll 360 brings the arrays 250 to a position 365 wherethey may be contacted by the flexible film 200. In still anotherembodiment (FIG. 7C) the arrays 250 may be moved in a linear fashion bya conveyer belt 370 so as to advance the arrays to a position where theymay be contacted by the flexible film 200. The arrays may also berotated about a central axis as described above. It should be understoodthat the foregoing embodiments are merely exemplary and any suitableconventional means of motion may be used to bring the flexible film intocontact with the microneedles.

In one embodiment where repeated transfer steps are performed, thecarrier fluid may be allowed to substantially completely evaporatefollowing a transfer step and before a subsequent transfer step. Inanother embodiment, the temporal spacing of subsequent transfer stepsmay be selected so that some or all of the carrier fluid deposited inprevious transfer steps remains on the microneedles.

The desired flexure angle may depend on a number of factors, includingthe type of material and thickness of the flexible film, the shape andtype of material of the microneedle array, the type of coating solution,the amount of coating solution to be applied, and the desired locationof the subsequent dried coating on the array. Although any flexure angleis suitable, the flexure angle is typically between 0° and 90°, oftenbetween 5° and 30°, and sometimes between 5° and 15°. The flexure anglemay be held at a single fixed value during one or more transfer steps orit may be varied during a transfer step or varied from one transfer stepto another.

The rate at which the flexible film is moved (also referred to as the‘transfer rate’) in relation to the microneedle array may vary, but istypically between 0.01 m/s and 10 m/s, often between 0.05 m/s and 1 m/s,and sometimes between 0.1 m/s and 0.5 m/s. The transfer rate may be heldat a single fixed value during one or more transfer steps or it may bevaried during a transfer step or varied from one transfer step toanother.

The amount of the coating solution applied to the flexible film may beadjusted depending on the desired amount of coating material to beapplied and the desired location of the subsequent dried coating on thearray. The coating solution will typically form a coating layer having athickness that is typically equal to or less than the height of themicroneedles and is often between 10 and 90% of the height of themicroneedles and sometimes between 30 and 50% of the height of themicroneedles. In some embodiments the coating layer will have athickness of between 20 and 200 microns and sometimes between 20 and 50microns. The coating solution may be applied to the flexible film by anyof a number of conventional methods used to coat flat substrates. It maybe desirable to use a coating method that provides a relatively evencoating thickness across the area of the flexible film that comes incontact with the microneedles during the transfer step. Alternatively,if a coating layer of uneven thickness is applied to the flexible film,then it may be desirable to include a step to make the thickness moreeven (such as doctoring) prior to the transfer step. The amount ofcoating solution transferred to the microneedles during a transfer stepis typically more than 0.1 μL, often between 0.1 μL and 10 μL, andsometimes between 0.5 μL and 2 μL.

The flexible film (i.e., coating substrate) may be any suitable flexiblematerial that can be contacted with the microneedle array withoutcausing undue damage to the delicate microneedles. Typical films may bethin polymeric or paper films. Suitable examples of thin polymeric filmsinclude nylon, polyethylene, polypropylene, polyurethane, andpolyethylene terephthalate. It may be desired to use a membranematerial, such as a nylon filter having 0.20 or 0.45 micron pores. Itmay be desirable for any porous features in the flexible film surface tobe smaller than the approximate size of the microneedle tips, so as toavoid any potential for mechanical interlocking between the microneedlesand the coating substrate. The desired thickness of the film will dependon the material of the film and the type of microneedles, but istypically less than 250 microns, sometimes less than 100 microns, andmay be less than 50 microns.

The area of the flexible film may vary depending on the size and shapeof the microneedle array to be coated. In one embodiment, the area ofthe film may be sufficient to coat more than one microneedle array in asingle transfer step. The flexible film may have any of a number ofdifferent shapes including, for example, a square, rectangle, circle, oroval.

In one embodiment, the shape of the flexible film is chosen so that ithas a uniform trailing edge, such as, for example, a film in the shapeof a square or rectangle. This may aid in providing a uniform coatingacross the width of the array. The area of a trailing edge of the filmthat comes in contact with the array will typically have a width similarto the widest dimension of the microneedle array to be coated and alength of between about 0.05 cm and 1.0 cm, often between about 0.05 cmand 0.5 cm, and sometimes between about 0.1 cm and 0.2 cm. In anotherembodiment, substantially the entire film area will come into contactwith the array, in which case the film typically has an area of betweenabout 0.2 and 1.5 times the area of the array, often between about 0.5and 1.2 times the area of the array, and sometimes an area about 1.0times the area of the array.

In one embodiment, the flexible film may be treated, such as with achemical or physical surface treatment, in order to control or enhancethe wetting properties of the coating solution on the coating substrate.For example, it may be desired to apply a hydrophilic surface treatmentto all or part of the coating substrate to enhance the wettingproperties of aqueous coating solutions. In one embodiment, a surfacetreatment may be applied such that only a portion of the leading edge ofthe flexible film is surface treated and substantially all of thetrailing edge of the flexible film is surface treated. Such adifferential treatment may aid in channeling coating solution from theleading edge to the trailing edge of the flexible film.

The coating solution comprises a carrier fluid or solvent and at leastone dissolved or dispersed coating material that will ultimately becomethe dried coating on the microneedle array. The coating solution maycomprise more than one dissolved coating material, more than onedispersed or suspended coating material, or a mixture of dissolved anddispersed coating materials. In one embodiment, the coating material maybe a therapeutic agent. The carrier fluid or solvent should be selectedsuch that it may dissolve or disperse the material intended for coating.Examples of suitable carrier fluids or solvents include water, ethanol,methanol, isopropanol, ethyl acetate, hexane, and heptane. The carrierfluid is evaporated after application to the microneedle array to leavedried coating material on the microneedle array. Evaporation may beallowed to take place at ambient conditions or may be adjusted byaltering the temperature or pressure of the atmosphere surrounding themicroneedle array. Evaporation conditions are desirably selected so asto avoid degradation of the coating material. The coating solution maycontain additional excipients including, for example, viscositymodifiers, stabilizers, and other additives. Examples of suitableadditional excipients include sucrose, ovalbumin, and hydroxyethylcellulose.

Dried coating material is deposited on the microneedle array uponevaporation of the transferred coating solution. In one embodiment, thedried coating material is preferentially deposited on the microneedles.By preferentially deposited it is meant that the amount of dried coatingper unit surface area will be greater on the microneedles than on thesubstrate. More preferably, the dried coating material is preferentiallydeposited on or near the tips of the microneedles. In some cases morethan half of the dried coating material by weight is deposited on themicroneedles. In some cases the dried coating preferentially resides onthe upper half of the microneedles, that is, the portion of themicroneedles away from the substrate. In one embodiment substantially nodried coating material is deposited on the substrate, that is,substantially all of the dried coating material is deposited on themicroneedles. In one embodiment, substantially all of the dried coatingmaterial is deposited on the upper half of the microneedles. Thethickness of the dried coating material may vary depending on thelocation on the microneedle array and the intended application use forthe coated microneedle array. Typical dried coating thicknesses are lessthan 50 microns, often less than 20 microns and sometimes less than 10microns. It may be desirable for the coating thickness to be smallernear the tip of the microneedle so as not to interfere with the abilityof the microneedle to effectively pierce into the skin.

FIG. 5 shows a scanning electron micrograph of a coated microneedlearray where the coated material has formed a “teardrop” shape near thetip of the microneedle. This shape may be particularly desirable as itconcentrates material near the tip of the microneedle, but does notappreciably alter the tip geometry, thus allowing for efficient piercingof the skin and delivery of coated material into the skin. The teardropshape may be generally characterized by the maximum dimension of thedried coating when observed from above (i.e., looking down at the shaftof the needle towards the microneedle array substrate) and the heightabove the substrate where the maximum dimension of the dried coatingoccurs.

In one embodiment, the dried coating material may contain apharmacological agent and the pharmacological agent is preferentiallydeposited on the microneedles. By preferentially deposited it is meantthat the amount of pharmacological agent per unit surface area will begreater on the microneedles than on the substrate. More preferably, thepharmacological agent is preferentially deposited on or near the tips ofthe microneedles. In some cases more than half of the pharmacologicalagent by weight is deposited on the microneedles. In some cases thepharmacological agent preferentially resides on the upper half of themicroneedles, that is, the portion of the microneedles away from thesubstrate. In one embodiment substantially no pharmacological agent isdeposited on the substrate, that is, substantially all of thepharmacological agent is deposited on the microneedles. In oneembodiment, substantially all of the pharmacological agent is depositedon the upper half of the microneedles.

In one embodiment, the microneedle array shown in FIGS. 1 and 2 may beapplied to a skin surface in the form of a patch shown in more detail inFIG. 4. FIG. 4 illustrates a microneedle device comprising a patch 20 inthe form of a combination of an array 22, pressure sensitive adhesive 24and backing 26. A portion of the array 22 is illustrated withmicroneedles 10 protruding from a microneedle substrate surface 14. Themicroneedles 10 may be arranged in any desired pattern or distributedover the microneedle substrate surface 14 randomly. As shown, themicroneedles 10 are arranged in uniformly spaced rows. In oneembodiment, arrays of the present invention have a distal-facing surfacearea of more than about 0.1 cm² and less than about 20 cm², preferablymore than about 0.5 cm² and less than about 5 cm². In one embodiment(not shown), a portion of the substrate surface 14 of the patch 20 isnon-patterned. In one embodiment the non-patterned surface has an areaof more than about 1 percent and less than about 75 percent of the totalarea of the device surface that faces a skin surface of a patient. Inone embodiment the non-patterned surface has an area of more than about0.10 square inch (0.65 cm²) to less than about 1 square inch (6.5 cm²).In another embodiment (shown in FIG. 4), the microneedles are disposedover substantially the entire surface area of the array 22.

A second aspect of the method of the present invention is shown in FIG.8A. A microneedle array 450 is provided having a substrate 420 andmicroneedles 430 extending from the substrate. A coating solution 410has been applied to the first major surface 405 of a flexible film 400.The coating solution 410 comprises a carrier fluid and a coatingmaterial. The flexible film 400 serves as a flexible coating substrateand is flexibly mounted to a rod 470. The film 400 is part of a dauberassembly 460 and held in place with an attachment band 472. As shown,the flexible film 400 is supported by a pad 480 positioned between therod 470 and the back of the flexible film 400, thus allowing flexuralmotion of the film 400.

The first major surface 405 of the flexible film 400 is brought intocontact with the microneedles 430 during a transfer step as shown inFIG. 8B, thereby bringing the coating solution 410 into contact with themicroneedles 430. The flexible film 400 is then removed from contactwith the microneedles 430 as shown in FIG. 8C, thereby transferring atleast a portion of the coating solution 410 to the microneedle array450. The transferred carrier fluid is then allowed to evaporate, therebyleaving a dried coating 412 on the microneedle array 450.

The flexible film 400 may be brought into contact with the microneedles430 by moving one or both of the dauber assembly 460 and/or themicroneedle array 450 towards each other. In one embodiment, themicroneedle array 450 is held fixed in place during the transfer stepand the dauber assembly 460 is moved in a direction generallyperpendicular to the plane of the microneedle array. The plane of themicroneedle array should be understood to be a plane generally definedby the tips of the microneedles. As shown in FIG. 8A, such a plane isparallel to the substrate 420 of the microneedle array 450. It should beunderstood that the tips of the microneedle array need not lie exactlywithin a single plane, but that a single plane will be at leastapproximately congruent with the tips of the microneedles.

The flexible film 400 may be supported and attached to the dauberassembly 460 by any suitable means. FIG. 9A shows the film 400 supportedby a column of air or other fluid 500 that is held under pressure withinthe rod 470, which is hollow in this embodiment. The air or fluid 500applies pressure in the direction of the arrow A against the film 400.FIG. 9B shows the film attached to the dauber assembly 460 by means of avacuum 520 that is drawn through an outer chamber 530 of the rod 470. Asshown, the rod is filled with a foam 540 that supports the film 400.Recessed areas 550 are provided within the supporting foam 540, whichmay facilitate compression of the foam during the transfer step. Anoptional supporting plate, such as a thin metal piece may be placedbetween the film 400 and the foam 540. FIG. 9C is a variation of theembodiment shown in FIG. 9B wherein the film 400 is thermoformed so asto provide a contoured surface. The outer edge 560 of the film 400serves to provide attachment to the rod 470 and the central area 570serves as the coating substrate. FIG. 9D shows a thermoformed film 400held in place at the outer edge 560 by an adhesive attachment 580. FIG.9E shows a film 400 that is formed as an integral part of the supportingfoam 540. Such an integral film may be formed by any conventional means,for example, by welding or gluing a film directly to a foam piece or bytreating the surface of a foam piece with heat or radiation to form asuitable film surface for use as a coating substrate.

A third aspect of the method of the present invention is shown in FIG.10A. A microneedle array 850 is provided having a substrate 820 andmicroneedles 830 extending from the substrate. A coating solution 810 isplaced in a coating reservoir block 802 having a coating substrate 804and walls 806. In one embodiment, the coating substrate 804 may be asmooth metal surface. In another embodiment, the coating substrate 804may be a thin, polymeric film or other flexible layer held against thetop surface of the coating reservoir block 802. The coating solution 810comprises a carrier fluid and a coating material. The coating solution810 may be metered onto the coating substrate 804, such that the coatingsolution has a desired thickness. Alternatively, an excess of coatingsolution may be applied to the coating substrate and the coatingsolution is then subsequently adjusted to the desired thickness byremoving fluid with a doctor blade. The flexible film 800 is flexiblymounted to a rod 870 and is part of a supporting assembly 860 and heldin place with an attachment band 872. As shown, the flexible film 800 issupported by a pad 880 positioned between the rod 870 and the back ofthe flexible film 800. The back of the microneedle array 850 (i.e., theportion of the microneedle array opposed to the microneedles) isattached to the flexible film 800. The microneedle array 850 is thusflexibly mounted to the supporting assembly 860. The supporting assembly860 and coating reservoir block 802 are brought towards each other suchthat the microneedle array 850 is brought into contact with the coatingsubstrate 804 during a transfer step as shown in FIG. 10B, therebybringing the coating solution 810 into contact with the microneedles830. The supporting assembly 860 is then removed from the coatingreservoir block 802 as shown in FIG. 10C, thereby transferring at leasta portion of the coating solution 810 to the microneedle array 850. Thetransferred carrier fluid is then allowed to evaporate, thereby leavinga dried coating 830 on the microneedle array 850. The microneedle array850 may be attached to the flexible film 800 by any conventional means,for example, by an adhesive bond or by a vacuum pulled through theflexible film 800 if the flexible film 800 is porous. In one embodiment,the microneedle array is temporarily attached to the flexible film 800,such as by a low-strength, repositionable adhesive. In anotherembodiment, the microneedle array may be permanently attached to theflexible film 800 in the form of a patch as described above. The patchbacking will thus serve as the flexible film 800 and may be temporarilyattached to the supporting assembly 860, such as by a vacuum.

When the coating solution is applied to a flexible film coatingsubstrate, any of a number of conventional means may be used. The amountof coating solution applied is desirably metered so as to provide acontrolled amount of coating solution on the coating substrate. Forexample, FIG. 11 shows use of an extrusion die 600 to directly applycoating solution 410 to a dauber assembly 460 having a flexible film 400coating substrate. Coating solution is fed into the extrusion die 600through an input line 602 and extruded out of a slot 604. The flexiblefilm 400 coating substrate with coating solution 410 is subsequentlymoved (e.g., along the direction of the arrow labeled B) and broughtinto contact with a microneedle array as described above after thecoating solution is applied.

In one embodiment, a pickup roller feed system with a cylindricalsurface onto which coating formulation is applied by any of severalmeans may be used to transfer coating solution to a flexible filmcoating substrate. This is typically done by passing the flexible filmover a pickup roller while the film is in slight contact with thesurface of the roller or the surface of the layer of coatingformulation. The surface of the pickup roller may rotate in the samedirection as the motion of the passing film, or in opposing direction,at matching surface speeds or at an optimal speed ratio for the desiredapplication volume. FIG. 12A shows use of a pickup roller 610 suppliedby direct contact with the surface of the coating formulation in asupply reservoir 612. A doctor blade 614 may be used to wipe off excessmaterial or meter the amount of material remaining on the surface of theroller. The doctor blade may be rigid or flexible (i.e. metallic orrubber), and may be in contact with or gapped slightly away from thesurface of the pickup roller. Alternatively (not shown), an extrusiondie or one or more micro tubes may be used to apply coating formulationdirectly to the surface of the pickup roller. The pickup roller 610 withapplied coating solution is allowed to rotate and come into contact withthe flexible film 400 coating substrate that is supported by a dauberassembly 460. FIG. 12B shows a similar example where the coatingsubstrate is a flexible film 400 held by an angled film holder 620. Inboth figures, the arrow labeled C shows the direction of rotation of thepickup roller 610. As in previous figures, the dauber assembly 460 orflexible film 400 may be moved into contact with a microneedle arrayusing any suitable means of motion.

FIG. 13 shows use of a partner roll 630 to contact the surface of thecoating formulation in the supply reservoir 612 while rotating in theopposite direction of the pickup roll 610 (direction of rotation of eachroll shown by large arrow), while the gap between the two rolls controlsthe amount of material remaining on the surface of the partner rollprior to it coming in contact with the flexible film. The pickup roller610 and partner roll 630 may be independently constructed of solid orconformable material (i.e. metal or rubber), and its surface may besmooth or it may be textured, for example, as a gravure roll or ananilox roll of a flexographic printer. Typically the partner roll 630contacting the coating formulation in the supply reservoir 612 is madeof a soft material which carries the coating formulation upward and intocontact with the pickup roller 610 which removes excess coatingformulation and subsequently transfers the metered coating formulationto the flexible film 400 coating substrate.

FIG. 14A shows a method of directly contacting the flexible film 400coating substrate of the dauber assembly 460 with the surface of acoating formulation in a supply reservoir 612. The dauber may then beremoved from the reservoir and passed over a doctoring blade 640, asshown in FIG. 14B, in order to wipe off excess coating formulation andthereby leave a desired thickness of coating formulation on the coatingsubstrate of the dauber assembly 460.

A pickup plate feed system is simply a surface onto which is appliedcoating formulation for subsequent transfer to a flexible film coatingsubstrate, typically by passing the flexible film over the pickup platewhile the flexible film is in slight contact with the surface of theplate. Typically flat and horizontal, the pickup plate may be suppliedwith coating formulation from above or below by any conventional means,such as with use of a pump and tubing or an extrusion die. FIG. 15A is aside view of a pump 650 and tube 652 that feed coating solution to thetop surface of a pickup plate 654. A flexible film 656 held by an angledfilm holder 658 is shown passing over the pickup plate 654. FIG. 15B isa top view of the pickup plate 654 showing the tube opening 660 andcapillary grooves 662 machined into the pickup plate in a herringbonepattern to serve as a means of spreading the coating formulation acrossthe surface of the pickup plate 654. Any other suitable means ofspreading the coating formulation on the surface of the pickup plate toa desired shape and size may be optionally employed, such as through useof an absorbent material, such as cheesecloth, applied to one end of thepickup plate. The absorbent material may lie on the surface of thepickup plate and wick the coating formulation uniformly outward from asupply orifice to a desired width for transfer. Absorbent material maybe used alone or in conjunction with capillary grooves in the surface ofthe plate. Feeding and spreading of the coating formulation on thepickup plate can also be accomplished by integrating an extrusion die670 into the bottom surface of the pickup plate 654 as shown in FIGS.16A, B. The outlet 672 of the extrusion die is sized and spacedappropriately to feed a desired amount of coating formulation to thepickup plate for transfer to a flexible film. An optional doctoringfeature for wiping excess coating formulation from the applicator may beused in conjunction with a pickup plate. FIG. 17A shows a sharpdoctoring feature 680 integrated directly into the pickup plate 654.FIG. 17B shows a rounded doctoring feature 682 integrated directly intothe pickup plate 654. Other suitable shapes, such as a bluntly serratedshape, may be used for the doctoring feature. Although the feedingmechanisms shown in FIGS. 15 to 17 are illustrated as transferringcoating solution to a flexible film held by an angled film holder, itshould be understood that these mechanisms are equally suitable fortransfer of coating solution to any type of flexible film, such as aflexible film supported by a dauber assembly as described above. Thetrailing edge will generally be aligned so that it moves in a planeparallel to the plane of the bottom surface of the pickup plate and willbe aligned in height so that it will interfere with the fluid on thepickup plate. In one embodiment, the trailing edge may be aligned sothat it moves in a plane that is below the bottom surface of the pickupplate, so that the trailing edge interferes with both the pickup plateand the coating fluid. This distance between the plane of motion of thetrailing edge and the top surface of the pickup plate is referred to asthe edge-plate interference and is typically between about 0 and about 2mm, sometimes between about 0 and about 1 mm.

In all of the foregoing embodiments the coating fluid may form arelatively thin film on the coating substrate just prior to a transferstep. The thickness of coating fluid on the coating substrate prior to atransfer step is typically less than or equal to the height of at leastone of the microneedles and often less than or equal to the height ofall of the microneedles. The thickness of coating fluid on the coatingsubstrate prior to a transfer step may be between about 25% and 75% ofthe height of the microneedles and sometimes between about 30% and 50%of the height of the microneedles. Adjustment of the coating fluidthickness to such dimensions may be particularly beneficial in allowingpreferential deposition of coating solution and coating material ontothe tips of the microneedles.

The viscosity of the coating fluid will depend on a number ofparameters, including the types and amounts of carrier fluid(s),dissolved or dispersed coating materials, and additional excipients, aswell as the temperature of the coating fluid. In one embodiment, it maybe desirable to cool the coating fluid to a temperature below room orambient temperature, but above the freezing point of the coating fluid.Such cooling may improve the ability to deposit a dried coating materialby, for example, increasing the viscosity of the coating fluid orreducing any tendency of the coating fluid to evaporate prior totransfer to the microneedle array. The temperature of the coating fluidmay be controlled by any of a number of conventional methods. Forexample, the environmental temperature surrounding the entire apparatusmay be controlled such that the coating fluid, coating substrate, andmicroneedle array are all held at a fixed, uniform temperature.Alternatively, various items may be selectively cooled, such as thecoating substrate, the microneedle array, a pickup roller or pickupplate, if employed, and/or the coating fluid reservoir. In oneembodiment the viscosity of the coating solution may be greater than orequal to the viscosity of water at ambient temperature (i.e., about 1centipoise or cP). Viscosity may be measured by any conventional means,such as with a cone and plate, controlled shear rate rheometer at agiven shear rate. In one embodiment, the viscosity at a shear rate of 50sec⁻¹ is greater than 4 cP, often greater than 10 cP, and sometimesgreater than 20 cP. In one embodiment, the viscosity at a shear rate of50 sec⁻¹ is less than 1500 cP, often less than 500 cP, and sometimesless than 100 cP.

The microneedle devices useful in the various embodiments of theinvention may comprise any of a variety of configurations, such as thosedescribed in the following patents and patent applications, thedisclosures of which are herein incorporated by reference. Oneembodiment for the microneedle devices comprises the structuresdisclosed in U.S. Pat. No. 6,881,203. The disclosed microstructures inthe aforementioned patent application are in the form of microneedleshaving tapered structures that include at least one channel formed inthe outside surface of each microneedle. The microneedles may have basesthat are elongated in one direction. The channels in microneedles withelongated bases may extend from one of the ends of the elongated basestowards the tips of the microneedles. The channels formed along thesides of the microneedles may optionally be terminated short of the tipsof the microneedles. The microneedle arrays may also include conduitstructures formed on the surface of the substrate on which themicroneedle array is located. The channels in the microneedles may be influid communication with the conduit structures. Another embodiment forthe microneedle devices comprises the structures disclosed in co-pendingU.S. Patent Application Publication No. 2005/0261631, which describesmicroneedles having a truncated tapered shape and a controlled aspectratio. Still another embodiment for the microneedle devices comprisesthe structures disclosed in U.S. Pat. No. 6,091,975 (Daddona, et al.)which describes blade-like microprotrusions for piercing the skin. Stillanother embodiment for the microneedle devices comprises the structuresdisclosed in U.S. Pat. No. 6,313,612 (Sherman, et al.) which describestapered structures having a hollow central channel. Still anotherembodiment for the micro arrays comprises the structures disclosed inInternational Publication No. WO 00/74766 (Gartstein, et al.) whichdescribes hollow microneedles having at least one longitudinal blade atthe top surface of tip of the microneedle.

The surface of the microneedles may be altered with a surfacepre-treatment, such as a plasma treatment capable of altering surfacefunctionality. For example, polycarbonate may be plasma treated with anitrogen plasma to cause amide functionalization or with an oxygenplasma to cause carboxylate functionalization. A combination of nitrogenand oxygen plasma treatment may be used to give a mixed surfacefunctionality. Alternatively, the surface of the microneedles may betreated with a coating to alter the surface properties. Such a coatingmay be directly applied as a solid material, such as through use of heator plasma deposition. Examples of thin layers of material cured onto thearray include plasma deposited diamond-like glass films, such as thosedescribed in U.S. Pat. No. 6,881,538 (Haddad, et al.), ultravioletpolymerized acrylates, such as those described in U.S. Pat. No.5,440,446 (Shaw, et al.), plasma deposited fluoropolymers, or any otherthin layer that may be applied by conventional coating method, such asspray coating or roll coating and subsequently crosslinked using anysuitable radiation. In one embodiment, a diamond-like glass film may bedeposited on the microneedles and subsequently treated with an oxygenplasma to make the surface hydrophilic.

Microneedle devices suitable for use in the present invention may beused to deliver therapeutic agents or drugs (including anypharmacological agent or agents) through the skin in a variation ontransdermal delivery, or to the skin for intradermal or topicaltreatment, such as vaccination.

In one aspect, drugs that are of a large molecular weight may bedelivered transdermally. Increasing molecular weight of a drug typicallycauses a decrease in unassisted transdermal delivery. Microneedledevices suitable for use in the present invention have utility for thedelivery of large molecules that are ordinarily difficult to deliver bypassive transdermal delivery. Examples of such large molecules includeproteins, peptides, nucleotide sequences, monoclonal antibodies, DNAvaccines, polysaccharides, such as heparin, and antibiotics, such asceftriaxone.

In another aspect, microneedle devices suitable for use in the presentinvention may have utility for enhancing or allowing transdermaldelivery of small molecules that are otherwise difficult or impossibleto deliver by passive transdermal delivery. Examples of such moleculesinclude salt forms; ionic molecules, such as bisphosphonates, preferablysodium alendronate or pamidronate; and molecules with physicochemicalproperties that are not conducive to passive transdermal delivery.

In another aspect, microneedle devices suitable for use in the presentinvention may have utility for enhancing or allowing transdermaldelivery of small molecules that are otherwise difficult or impossibleto deliver by passive transdermal delivery. Examples of such moleculesinclude salt forms; ionic molecules, such as bisphosphonates, preferablysodium alendronate or pamidronate; and molecules with physicochemicalproperties that are not conducive to passive transdermal delivery.

In another aspect, microneedle devices suitable for use in the presentinvention may have utility for enhancing delivery of molecules to theskin, such as in dermatological treatments, vaccine delivery, or inenhancing immune response of vaccine adjuvants. Examples of suitablevaccines include flu vaccine, Lyme disease vaccine, rabies vaccine,measles vaccine, mumps vaccine, chicken pox vaccine, small pox vaccine,hepatitis vaccine, pertussis vaccine, rubella vaccine, diphtheriavaccine, encephalitis vaccine, yellow fever vaccine, recombinant proteinvaccine, DNA vaccine, polio vaccine, therapeutic cancer vaccine, herpesvaccine, pneumococcal vaccine, meningitis vaccine, whooping coughvaccine, tetanus vaccine, typhoid fever vaccine, cholera vaccine,tuberculosis vaccine, and combinations thereof. The term “vaccine” thusincludes, without limitation, antigens in the forms of proteins,polysaccharides, oligosaccharides, or weakened or killed viruses.Additional examples of suitable vaccines and vaccine adjuvants aredescribed in U.S. Patent Application Publication No. 2004/0049150, thedisclosure of which is hereby incorporated by reference.

Microneedle devices may be used for immediate delivery, that is wherethey are applied and immediately removed from the application site, orthey may be left in place for an extended time, which may range from afew minutes to as long as 1 week. In one aspect, an extended time ofdelivery may be from 1 to 30 minutes to allow for more complete deliveryof a drug than can be obtained upon application and immediate removal.In another aspect, an extended time of delivery may be from 4 hours to 1week to provide for a sustained release of drug.

EXAMPLES Tetanus Toxoid Total-Array Content by High Performance LiquidChromatography (HPLC)

A sample extraction solvent was prepared containing 50 mM potassiumperchlorate, 50 mM potassium citrate, 20 mM sodium phosphate, 376 mMsodium chloride, and 100 μg/mL bovine serum albumin. An HPLC samplesolution was prepared by placing an array into a polypropylene cup,adding 1.0 mL of the sample extraction solvent to the cup, snapping acap onto the sample cup, and sonicating for 30 minutes.

Gradient elution HPLC (Mobile phase A): 0.2% (v/v) perchloric acid;Mobile phase B: 10% water, 88% acetonitrile, 2% isopropanol, 0.2%perchloric acid (70%); Solvent Program: 0.00 min, 22% B, 1.0 mL/min;6.00 min, 58% B, 1.0 mL/min; 6.01 min, 100% B, 1.0 mL/min; 6.50 min,100% B, 0.5 mL/min; 10.0 min, 0% B, 0.5 mL/min; Injection Volume: 100μL; Column: Zorbax 300SB-C8 50×4.6 mm, 3.5 micron) was used to quantifytetanus toxoid in the HPLC sample solution.

Non-adjuvanted tetanus toxoid (TT) vaccine (Aventis) was calibratedagainst a lyophilized TT primary standard (List Biologics) and used as aworking standard. The working standard was used to obtain a calibrationcurve from approximately 1 μg-TT/mL to 28 μg-TT/mL. The correlationcoefficient for the linear regression of the calibration curve wastypically greater than 0.999. Tetanus toxoid content results are theaverage of between 6 and 10 replicates.

Tetanus Toxoid Tip-Content by High Performance Liquid Chromatography(HPLC)

Tetanus toxoid content on the tips of the microneedles was measured byfixing the toxoid in place on the substrate and lower portions of themicroneedles so that it could not be extracted into the HPLC samplesolution. A microneedle array was placed on a flat surface with theneedles pointing upward and 10 μL of an oil-based polyurethane coatingsolution (Minwax® Fast-Drying Polyurethane) was applied to the array andallowed to coat the substrate of the array. The polyurethane was allowedto cure for at least 3 hours at ambient conditions. The array wassubsequently extracted and analyzed as described in the total contentmethod.

Aluminum Content by Inductively Coupled Plasma (ICP)

A 0.5 mL aliquot of the HPLC sample solution (described above) wasdiluted to 5.0 mL with 4% nitric acid for analysis of aluminum by ICP.The analysis was calibrated by using aluminum standards at 1, 2, 4, 5,6, 8 and 11 μg/mL. The correlation coefficient for the linear regressionof the calibration curve was typically greater than 0.999.

Enzyme-Linked Immunosorbent Assay (ELISA)

Quantitative determination of anti-tetanus toxoid IgG from rabbit serumwas performed by ELISA. Tetanus toxoid is coated on the solid phase andbinds anti-tetanus toxoid IgG from rabbit serum samples. Plates arewashed and bound rabbit IgG is detected with an anti-rabbit IgG-HRPconjugate. The assay was standardized against the EP veterinary standardrabbit anti-tetanus toxoid BRP Batch 1 (EDQM-European PharmacopeiaCommission catalog number C2425600). 1000 arbitrary units (AU) from thisELISA is equivalent to 1 international unit (IU). Unless otherwisenoted, anti-tetanus toxoid IgG results are reported as the geometricaverage of 5 replicates.

Microneedle Arrays

Microneedle arrays were prepared as follows. A circular disk (area 2cm², thickness 1.02 mm) that was partially patterned with an array ofmicroneedles (37×37) in a square shape (1 cm²) centered on one side ofthe disk was prepared. The needles were regularly spaced with a distanceof 275 microns between the tips of adjacent needles in a square-shapedpattern. Individual needles were pyramidal in shape with a height of 250microns and a square base having a side-length of 83.3 microns. The tipswere truncated with a flat, square-shaped top having a side-length of 5microns. Arrays were injection molded according to the generaldescription provided in International Patent Application Publication No.WO 05/82596 and made from polycarbonate (Lexan® HPS1R-1125, GE Plastics,Pittsfield, Mass.). The center of the disk was then die cut to provide amicroneedle array (area=1 cm²) having microneedles on approximately 90%of the surface of the patterned side of the disk. The microneedle arrayhad approximately 1200 microneedles.

Example 1

A stock coating formulation was prepared as follows. An aluminumhydroxide adjuvant (Alhydrogel 85™, Brenntag Biosector Co. Denmark) wasused for adsorption of tetanus toxoid according to the procedureprovided by the manufacturer. An amount (5 mL) of tetanus toxoid (TT)(Statens Serum Institute Lot 92-1, 888 Lf/mL) was added dropwise toaluminum hydroxide adjuvant (5 mL) solution while vortexing for 2minutes. The adsorption process was continued by mixing the formulationfor another 20 minutes at room temperature using a horizontal shaker.The mixture was then desalted and concentrated by centrifugation. Afterfinal centrifugation at 2000 rpm for 10 min, the precipitate of adsorbedTT was resuspended in sucrose solution to provide a 14% (w/v) sucrosesolution of adjuvanted tetanus toxoid. All formulations were stored at4° C.

Microneedle arrays were prepared as described above and treated asfollows. The arrays were plasma treated using a Plasma-Therm VII 7000series plasma processing system. A diamond-like glass thin film wasformed through plasma deposition by feeding a mixture of tetramethylsilane (150 standard cubic centimeter per minute, sccm) and oxygen (200sccm) gas in an unpressurized plasma with 2000 W RF power applied for 15seconds. The arrays were then subsequently treated with an oxygen plasma(400 sccm) under a pressure of 150 mTorr with 300 W power for 60 secondsto remove elemental and covalently bonded carbon from the surface atomiclayers and to make the surface hydrophilic.

An apparatus as generally shown in FIG. 3A, B with a flexible film asshown in FIG. 1 was used to apply the coating formulation to themicroneedle arrays. The flexible film was a nylon filter membrane (127μm thick) with 0.45 micron pore size (Alltech Associate, Inc.) that wasmounted to a rotational arm aligned so as to rotate in a plane parallelto the surface of the microneedle array to be coated. The portion of theflexible film extending from the rotational arm was approximately 1.5 cmwide by 0.75 cm long. A supporting piece of polyester (76 μm thick,44125 green color coded plastic shim, Precision Brand Products) wasmounted behind the nylon filter membrane. The supporting polyester piecewas approximately 1.5 cm wide by 0.55 cm long and aligned so that thetrailing edge of the flexible film extended about 0.2 cm beyond thetrailing edge of the polyester film piece. The arm was aligned so thatthe trailing edge of the flexible film was approximately 0.035 inch (889μm) below the plane formed by the tips of the microneedles on the array.The flexure angle of the film was approximately 15 degrees.

A pickup plate, as generally shown in FIG. 17B was used to applysolution to the flexible film. The arm was aligned so that the trailingedge of the flexible film was moved in a plane parallel to and adistance below the plane of the top surface of the pickup plate. Thisdistance, referred to as the edge-plate interference, was 0.030 inch(762 μm). The trailing edge thus interfered with the top surface of thepickup plate. Coating formulation was applied to the top surface of thepickup plate and transferred to the flexible film. Before each transferstep, approximately 5 μL of the coating formulation was applied to thepickup plate. The flexible film was advanced over the surface of thearray at a speed of approximately 9 cm/sec so that the trailing edge ofthe film contacted the needle tips and was brushed over the surface ofthe array. The array was rotated 90 degrees in between each individualtransfer step. The transfer step was repeated 5-8 times until driedformulation in a teardrop shape with an approximate maximum dimension of70 microns was formed at a height on the microneedles of approximately100 to 125 microns above the substrate of the microneedle array. Thecoated arrays were allowed to dry at room temperature and humidity.

Tetanus toxoid total-array content as measured by reversed phase HPLCwas 9.5 μg (st. dev.=4.6 μg). Aluminum content of the coated array asmeasured by ICP was 12 μg (st. dev.=5 μg).

Example 2

Coated microneedle arrays were prepared as in Example 1 with theexception that the amount of tetanus toxoid was reduced by half. Tetanustoxoid total-array content as measured by reversed phase HPLC was 5.7 μg(st. dev.=1.2 μg). Aluminum content of the coated array as measured byICP was 8 μg (st. dev.=4 μg).

In Vivo Anti-Tetanus Toxoid IgG and Tetanus Toxoid Removal

Microneedle devices were prepared by adhering antigen coated arrays asdescribed in Examples 1 to 3 to an adhesive backing. The arrays wereapplied to New Zealand White female rabbits (N=5) using an applicator asgenerally described in PCT Publication No. WO 2005/123173, thedisclosure of which is hereby incorporated by reference. The applicatorpiston mass was 2.88 g and the devices were applied at a velocity of6.19 meters/second. An area on the abdomen of each rabbit was closelyclipped and shaved, taking care not to irritate the skin. One device wasapplied to each rabbit and allowed to remain in place for 20 minutesbefore removal. A second device (with the same coating as the firstdevice) was applied to each rabbit 14 days after the initial applicationand again allowed to remain in place for 20 minutes before removal. Aserum sample was taken from each rabbit 21 days after the initialapplication and analyzed for the level of anti-tetanus toxoid IgG byELISA. The anti-tetanus toxoid IgG results are reported as the geometricmean of the 5 replicates. The results are summarized in Table 1. Theresidual amount of tetanus toxoid in the arrays removed from the rabbitswas tested by HPLC. The amount of tetanus toxoid removed from the arraywas determined by taking the difference between the initial tetanustoxoid level and the residual tetanus toxoid level. The results aresummarized in Table 1.

In addition, testing (indicated below as 2×) was performed where twoarrays were applied to each rabbit at each application time, thusproviding a double dose. Amount of tetanus toxoid removed is reported asthe total removed from both arrays.

TABLE 1 Array anti-tetanus tetanus toxoid removed Example No. toxoid IgG[AU] [μg] 1 4573 2.6 1 (2X) 6532 6.2 2 1187 3.1 2 (2X) 5547 5.8

Example 3

An antigen coating formulation was prepared as follows. Tetanus toxoid(Statens Serum Institute Lot 92-1, 888 Lf/mL) was concentrated bycentrifugation with a 30,000 g/mol MW cut-off membrane to provide aconcentrated tetanus toxoid stock solution (3554 Lf/mL). A 70% (w/v)sucrose stock solution was prepared. An aliquot (1.124 mL) of tetanustoxoid stock solution, an aliquot (5.179 mL) sucrose stock solution, andwater (0.930 mL) were added together and mixed to form the antigencoating formulation. The nominal sucrose concentration was 50% (w/v).

An apparatus as generally shown in FIG. 3A, B with a flexible film asshown in FIG. 1 was used to apply the coating formulation to themicroneedle arrays. A diamond-like glass film was deposited and treatedas described in Example 1. The flexible film was a nylon filter membrane(127 μm thick) with 0.45 micron pore size (Alltech Associate, Inc.,Deerfield, Ill.) that was mounted to a rotational arm aligned so as torotate in a plane parallel to the surface of the microneedle array to becoated. The portion of the flexible film extending from the rotationalarm was approximately 1.5 cm wide by 0.75 cm long. A supporting piece ofpolyester (76 μm thick, 44125 green color coded plastic shim, PrecisionBrand Products) was mounted behind the nylon filter membrane. Thesupporting polyester piece was approximately 1.5 cm wide by 0.55 cm longand aligned so that the trailing edge of the flexible film extended 0.20cm beyond the trailing edge of the polyester film piece. The arm wasaligned so that the trailing edge of the flexible film moved in a planeparallel to approximately 0.015 inch (381 μm) below the plane formed bythe tips of the microneedles on the array. This distance is referred toas the edge-array interference. The flexure angle of the film wasapproximately 7 degrees.

A pickup plate, as generally shown in FIG. 17B was used to applysolution to the flexible film. The arm was aligned so that the trailingedge of the flexible film moved in a plane 0.030 inch (762 μm) below theplane of the top surface of the pickup plate (i.e., the edge-plateinterference was 762 μm). Coating formulation (7 μL) was applied to thetop surface of the pickup plate. The flexible film was advanced over thesurface of the pickup plate at a speed of approximately 9 cm/sec so thatthe trailing edge of the film contacted the coating formulation in orderto transfer coating formulation to the flexible film. The flexible filmwas then advanced over the surface of the array at a speed ofapproximately 9 cm/sec so that the trailing edge of the film contactedthe needle tips and was brushed over the surface of the array. The stepof transferring fluid from the pickup plate to the film and subsequentlyto the array was repeated 4 to 6 times until the coating formulation wasused up. The array was rotated 90 degrees in between each individualtransfer step. Tetanus toxoid total-array content as measured byreversed phase HPLC was 12.9 μg (st. dev.=5.2 μg).

Examples 4-9

An antigen coating formulation was applied to microneedle arraysaccording to the procedure described in Example 3 with the exceptionthat one or more of the following parameters was varied: flexure angle,edge-array interference, edge-plate interference, stroke rate. Theparameter values and the resultant tetanus toxoid total-array contentsas measured by reversed phase HPLC are shown in Table 2.

TABLE 2 film tetanus Exam- flexure edge-array edge-plate velocity toxoidple angle interference, interference, [cm/ content No. [degrees] inch[μm] inch [μm] sec] [μg] 4 7 0.005 [127] 0.030 [762] 9 8.7 (2.4) 5 70.015 [381] 0.030 [762] 15 21.3 (12.5) 6 15 0.035 [889] 0.000 15 10.0(5.6)  7 15 0.005 [127] 0.000 9 7.6 (4.6) 8 15 0.035 [889] 0.030 [762] 96.5 (1.1) 9 15 0.005 [127] 0.030 [762] 9 8.0 (1.7)

Example 10

A coating solution was prepared as follows. Approximately equal amountsof sucrose and water were mixed along with a small amount of green foodcoloring (approximately 0.25% by volume) to aid in visualization. Thesolution was heated to 235° F. (112.8° C.) to form a sucrose solutionhaving about 75 to 80% solids, cooled for at least 12 hours and decantedto separate the sucrose solution from the undissolved or recrystallizedsolids.

A coating apparatus as generally described in FIG. 12A was used to applythe coating solution to a microneedle array. The dauber assembly wasprepared by adhering a 0.625 inch (1.59 cm) diameter×0.020 inch (0.051cm) thick disk of double-sided, medium density polyethylene foam tape(3M Cushion-Mount™ Plus no. 1020) to one end of a 0.65 inch (1.65 cm)diameter×2.0 inch (5.08 cm) long polyurethane foam rod (Aquazone®,density=1.8 lb/cu. Ft, 25% compression deflection of 0.56 psi (3.86 kPa)as tested by ASTM D 3574, Foamex International Inc., Linwood, Pa.). A0.20 inch (0.51 cm) thick×0.625 (1.59 cm) inch diameter brass disk wasadhered to the exposed side of the double-sided foam tape. Another diskof foam tape was adhered to the brass disk and a 0.005 inch (127 μm)thick×0.625 (1.59 cm) inch diameter piece of Nylon filtration membrane(0.45 μm pore size, Alltech Associate, Inc., Deerfield, Ill.) wasadhered to the exposed side of the second piece of double-sided foamtape. The laminate construction was thus: foam rod/foam tape/brassdisk/foam tape/nylon membrane. A 1.020 inch (2.59 cm) diameter groovedroll with a face width of 1 inch (2.54 cm) was used as the pickup roll.The pickup roll had a groove spacing of 0.012 inch (305 μm), grooveangle of 90 degrees, a nominal groove depth of 0.0060 inch (152 μm), anda nominal groove volume of 0.00360 cubic inch per square inch (0.00914mL per cm²) of roll surface. The pickup roll was centered in a reservoirtrough holding the coating solution described above. The reservoirtrough was cylindrical in shape with a diameter of 1.062 inch (2.70 cm).The doctor blade was a 0.0625 inch (0.159 cm) thick polyurethane sheetwith a Shore A hardness of 95 and was held in place by a 0.0625 inch(0.159 cm)×0.5 inch (1.27 cm) strip of stainless steel.

Coating solution was applied to the nylon membrane of the dauberassembly as generally shown in FIG. 12A. The pickup roll was rotated soas to fill the grooves with coating solution. The doctor blade wasplaced into contact with the pickup roller. The nylon membrane was thenpassed over the surface of the grooved roll several times until theamount of coating formulation on the nylon membrane reached equilibrium.The dauber assembly with coating fluid was then translated to a coatingstation where it was positioned directly above a microneedle array. Itwas then moved vertically to bring it into contact with the array asdepicted in FIGS. 8A-C, subsequently cycled up and down a specifiednumber of times in order to deposit coating formulation on the array,and then allowed to dry at ambient conditions. The microneedle arrayexhibited a light green color indicating that the sucrose solution wascoated on the array after 12 deposition cycles. Microscopic examinationshowed that the coating was deposited in a generally spherical shape ator near each microneedle tip with an approximate diameter of 30 to 50μm.

Example 11

A microneedle array was coated as described in Example 10 with thefollowing exceptions. The pickup roll had a groove spacing of 0.012 inch(305 μm), groove angle of 60 degrees, a nominal groove depth of 0.0104inch (264 μm), and a nominal groove volume of 0.00624 cubic inch persquare inch (0.01584 mL per cm²) of roll surface. The microneedle arrayexhibited a strong, non-uniform green color after 4 deposition cycles.Microscopic examination showed that the coating was deposited in agenerally spherical shape at or near each microneedle tip with anapproximate diameter of 30 to 80 μm.

Example 12

A microneedle array was coated as described in Example 11 with theexception that 10 deposition cycles were used. The microneedle arrayexhibited a strong, uniform green color. Microscopic examination showedthat the coating was deposited in a generally spherical shape at or neareach microneedle tip with an approximate diameter of 60 to 100 μm.

Example 13

A microneedle array was coated as described in Example 11 with theexception that the doctor blade was spaced about 1 mil (25 μm) away fromthe pickup roller and a single deposition cycle was used. Themicroneedle array exhibited a light, uniform green color. Microscopicexamination showed that the coating was deposited in a generallyteardrop shape at or near each microneedle tip with an approximatediameter (measured in a plane parallel to the array substrate at thewidest part of the teardrop) of 30 to 50 μm.

Example 14

A microneedle array was coated as described in Example 10 with thefollowing exceptions. The pickup roll had a groove spacing of 0.014 inch(356 μm), groove angle of 90 degrees, a nominal groove depth of 0.0070inch (178 μm), and a nominal groove volume of 0.00490 cubic inch persquare inch (0.02156 mL per cm²) of roll surface. The microneedle arrayexhibited a light, non-uniform, green color after 8 deposition cycles.Microscopic examination showed that the coating was deposited in agenerally spherical shape at or near each microneedle tip with anapproximate diameter of 30 to 60 μm.

Example 15

A microneedle array was coated as described in Example 14 with theexception that the doctor blade was spaced about 2 mil (50 μm) away fromthe pickup roller and a single deposition cycle was used. Themicroneedle array exhibited a light, uniform green color. Microscopicexamination showed that the coating was deposited in a generallyteardrop shape at or near each microneedle tip with an approximatediameter (measured in a plane parallel to the array substrate at thewidest part of the teardrop) of 40 to 50 μm.

Example 16

A microneedle array is coated as follows. A coating apparatus asgenerally described in FIG. 10A is used to apply a coating solution to amicroneedle array. The supporting assembly is prepared by adhering a0.625 inch (1.59 cm) diameter×0.020 inch (0.051 cm) thick disk ofdouble-sided, medium density polyethylene foam tape (3M Cushion-Mount™Plus no. 1020) to one end of a 0.65 inch (1.65 cm) diameter×2.0 inch(5.08 cm) long polyurethane foam rod (Aquazone®, density=1.8 lb/cu. Ft,25% compression deflection of 0.56 psi (3.86 kPa) as tested by ASTM D3574, Foamex International Inc., Linwood, Pa.). The non-patterned sideof a microneedle array is adhered to the exposed surface of thedouble-sided foam tape.

A stainless steel reservoir is used having a trough-shaped reservoirlarge enough to allow the microneedle array to be placed fully withinthe trough. Another disk of foam tape is adhered to the trough of thereservoir and a 0.005 inch (127 μm) thick×0.625 (1.59 cm) inch diameterpiece of Nylon filtration membrane (0.45 μm pore size, AlltechAssociate, Inc., Deerfield, Ill.) is adhered to the exposed side of thesecond piece of double-sided foam tape. An excess of coating solution isapplied to the Nylon filtration membrane and adjusted to a thickness ofabout one-half the height of the microneedles by removing excess fluidwith a doctor blade. The coating solution is an aqueous sucrose solutionhaving from 40 to 70% (w/w) sucrose. A transfer step is performed bybringing the supporting assembly towards the reservoir so that themicroneedles come into contact with both the Nylon filtration membraneand the coating solution. The supporting assembly is then removed fromcontact with the Nylon filtration membrane and the coating solution. Thearray is allowed to dry under ambient conditions. Repeated transfersteps may be employed to transfer additional coating material until thedried coating material forms a teardrop shape near the tip of eachmicroneedle.

The present invention has been described with reference to severalembodiments thereof. The foregoing detailed description and exampleshave been provided for clarity of understanding only, and no unnecessarylimitations are to be understood therefrom. It will be apparent to thoseskilled in the art that many changes can be made to the describedembodiments without departing from the spirit and scope of theinvention. Thus, the scope of the invention should not be limited to theexact details of the compositions and structures described herein, butrather by the language of the claims that follow.

We claim:
 1. A method of coating a microneedle array comprising: providing a microneedle array having a substrate and a plurality of microneedles; applying a coating solution comprising a carrier fluid and a coating material onto a first major surface of a flexible film; performing a transfer step of bringing the first major surface of the flexible film into contact with the microneedles and removing the flexible film from contact with the microneedles, wherein at least a portion of the coating solution is transferred to the microneedle array during the transfer step, and wherein the flexible film is moved in a linear direction across the microneedles while the coating solution on the first major surface of the flexible film is in contact with the microneedles; and allowing the carrier fluid to evaporate to leave a dried coating on the microneedle array.
 2. A method as claimed in claim 1, wherein the flexible film and the microneedle array define an angle of flexure during the transfer step that is between 0 and 90 degrees.
 3. A method as claimed in claim 2 wherein the angle of flexure is between 5 and 15 degrees.
 4. A method as claimed in claim 1 wherein the linear direction is selected from the group consisting of generally parallel to the plane of the microneedle array and generally perpendicular to the plane of the microneedle array.
 5. A method as claimed in claim 1 wherein more than one transfer step is performed.
 6. A method as claimed in claim 4 wherein more than one transfer step is performed and in between repeated transfer steps the microneedle array is rotated with respect to the flexible film in a plane generally parallel to the plane of the microneedle array substrate.
 7. A method as claimed in claim 1 wherein the amount of coating solution transferred to the microneedles during a transfer step is between 0.1 μL and 10 μL.
 8. A method as claimed in claim 1 wherein more than 50% by weight of the dried coating applied to the microneedle array is present on the needles.
 9. A method as claimed in claim 1 wherein the dried coating material is preferentially deposited onto the microneedles.
 10. A method as claimed in claim 1 wherein the dried coating material is preferentially deposited onto the upper half of the microneedles.
 11. A method as claimed in claim 1 wherein the coating solution comprises a therapeutic agent.
 12. A method as claimed in claim 11 wherein the therapeutic agent is present in the coating solution as a dispersed or suspended material.
 13. A method as claimed in claim 1 wherein the coating solution comprises water.
 14. A method as claimed in claim 1 wherein the coating solution comprises a vaccine, vaccine adjuvant, or mixture thereof.
 15. A method as claimed in claim 1 wherein the surface of the microneedles is hydrophilic.
 16. A method as claimed in claim 1 wherein the surface of the microneedles is coated with a thin film of diamond-like glass.
 17. A method of coating a microneedle array comprising: providing a microneedle array having a substrate and a plurality of microneedles; applying a coating solution comprising a carrier fluid and a coating material onto a first major surface of a flexible film; performing a transfer step of bringing the first ma or surface of the flexible film into contact with the microneedles and removing the flexible film from contact with the microneedles, wherein at least a portion of the coating solution is transferred to the microneedle array during the transfer step, and wherein the flexible film and the microneedle array define an angle of flexure during the transfer step that is between 5 and 15 degrees; and allowing the carrier fluid to evaporate.
 18. A method of coating a microneedle array comprising: providing a microneedle array having a substrate and a plurality of microneedles, wherein the surface of the microneedles is coated with a thin film of diamond-like glass; applying a coating solution comprising a carrier fluid and a coating material onto a first major surface of a flexible film; performing a transfer step of bringing the first ma or surface of the flexible film into contact with the microneedles and removing the flexible film from contact with the microneedles, wherein at least a portion of the coating solution is transferred to the microneedle array during the transfer step; and allowing the carrier fluid to evaporate.
 19. A method of coating a microneedle array comprising: providing a microneedle array having a substrate and a plurality of microneedles; providing a coating solution comprising a carrier fluid and a coating material; providing a coating apparatus comprising a coating substrate and a supporting member for the microneedle array, wherein at least one of the coating substrate and the microneedle array is flexibly mounted within the coating apparatus; applying the coating solution onto a first major surface of the coating substrate to form a layer of applied coating solution having a thickness equal to or less than the height of at least one of the microneedles, wherein the coating solution is applied to the first major surface of the coating substrate with a pickup plate or an extrusion die; performing a transfer step of bringing the first major surface of the coating substrate into contact with the microneedles and removing the coating substrate from contact with the microneedles, thereby transferring at least a portion of the coating solution to the microneedle array; and allowing the transferred carrier fluid to evaporate.
 20. A method as claimed in claim 19 wherein the coating substrate is flexibly mounted.
 21. A method as claimed in claim 20 wherein the coating substrate is a flexible film.
 22. A method as claimed in claim 21 wherein the first major surface of the coating substrate has a leading edge and a trailing edge and wherein the trailing edge of the flexible film is brought into contact with the microneedles during the transfer step.
 23. A method as claimed in claim 21 wherein the microneedle array is oriented so that the microneedles are facing upward and the coating solution on the flexible film is facing downwards when it is brought into contact with the microneedles.
 24. A method as claimed in claim 19 wherein the microneedle array is flexibly mounted.
 25. A method as claimed in claim 24 wherein the coating substrate is a fixed surface.
 26. A method as claimed in claim 25 wherein an excess of coating solution is applied to the coating substrate and a doctoring step is performed to provide the layer of applied coating solution having a thickness equal to or less than the height of at least one of the microneedles.
 27. A method as claimed in claim 24 wherein the coating substrate is flexibly mounted.
 28. A method as claimed in claim 19 wherein at least a portion of the first major surface of the coating substrate is hydrophilic.
 29. A method as claimed in claim 19 wherein the entire portion of the first major surface of the coating substrate is hydrophilic. 